Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the human central nervous system and the most common cause of non- traumatic neurological disability among young adults in North America. While axons were initially thought to be spared from destruction in MS, recent clinical, magnetic resonance imaging, and histopathological studies support significant axonal loss of pathology in MS lesions. This proposal is based on the hypothesis that axonal transection is the major cause of irreversible neurological defects in MS patients. Studies take advantage of a unique collection of MS tissue obtained by rapid autopsy and animal models of inflammatory demyelination and CNS trauma. The long-range goal of this proposal is to determine if neuroprotective agents and strategies to enhance remyelination should be added to the present arsenal of anti-inflammatory and immune modulating MS treatments. To each this goal, e have designed a series of experiments that will address fundamental unanswered questions regarding axonal loss and oligodendrocyte progenitor cells in MS lesions. Studies in Aim 1 will quantify axons in MS spinal cords and correlate the extent of axonal loss in MS spinal cords with tissue levels of N-acetyl-aspartic acid (NAA), a neuronal marker that is used for non-invasive monitoring of axonal pathology in MS patients. To complement studies of MS spinal cords, studies will characterize the time sequence of axonal changes following traumatic transection of rat spinal cord (Aim 2) and during chronic relapsing/remitting experimental allergic encephalomyelitis (Aim 3), an experimental model of MS that has significant of inflammatory demyelination and axonal pathology in spinal cord. Remyelination could protect axons and oligodendrocytes from precursor cells. While acute but not chronic MS lesions remyelinate, both types of lesion contain cells with characteristics of oligodendrocyte precursors. Studies in Aim 4 will characterize the distribution and determine if functional subpopulations of putative oligodendrocyte precursor cells exist in acute and chronic MS lesions. Collectively these studies will advance our knowledge of the pathogenesis of neurological disability in MS and provide direction for novel MS therapeutics.